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Maternal Hypertension and Neonatal Outcome Among Small for Gestational Age Infants

From the Department of Obstetrics and Gynaecology, University of British Columbia, and BC Women's Hospital and Health Centre, Vancouver; Centre for Healthcare Innovation and Improvement, British Columbia Research Institute for Children's and Women's Health, University of British Columbia, Vancouver; Department of Medicine, University of British Columbia, and BC Women's Hospital and Health Centre, Vancouver; Department of Neurobiology and Behavior, Mudd Hall, Cornell University, Ithaca, New York; and Department of Paediatrics, University of British Columbia, Vancouver, British Columbia.

	ABSTRACT

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

 
Objective: To determine whether maternal hypertension might improve perinatal outcome among small for gestational age (SGA) infants (< 10th percentile).

Methods: Our prospective cohort comprised 17 Canadian neonatal intensive care units (NICUs) and 3,244 SGA singletons. Multivariable regression was used to analyze the relation between maternal hypertension and each of the following: SNAP-II (Score of Neonatal Acute Physiology; ordinal regression) and neonatal survival and survival without severe intraventricular hemorrhage (logistic regression), adjusting for potential confounders.

Results: There were 698 (21.5%) neonates born to hypertensive mothers. Inversely associated with lower SNAP-II scores (healthier infant) were antenatal steroids (complete course: odds ratio [OR] 0.67, 95% confidence interval [CI] 0.54–0.83; incomplete: OR 0.71, 95% CI 0.56–0.88), lower gestational age (< 27 weeks: OR 0.06, 95% CI 0.05–0.08; 27–28 weeks: OR 0.11, 95% CI 0.07–0.17; 29–32 weeks: OR 0.28, 95% CI 0.23–0.35), 5-minute Apgar < 7 (OR 0.30, 95% CI 0.25–0.36), male gender (OR 0.80, 95% CI 0.70–0.92), and anomalies (OR 0.49, 95% CI 0.41–0.58). Maternal hypertension was associated with lower SNAP-II (healthier infant) (7.54 ± 11.16 [hypertensive] versus 7.21 ± 11.85 [normotensive]) on multivariable regression analysis (adjusted OR 1.25, 95% CI 1.05–1.49), as well as higher neonatal survival (93.0% versus 91.2%, and adjusted OR 1.9, 95% CI 1.2–3.0), but not survival without severe intraventricular hemorrhage (91.4% versus 87.0%, and adjusted OR 1.4, 95% CI 1.0–2.0), respectively.

Conclusion: Among SGA neonates in NICU, maternal hypertension is associated with improved admission neonatal physiology and survival.

Level of Evidence: II-2

Recent work has suggested that women with mild pregnancy-induced hypertension may have improved perinatal outcomes when compared with those either without hypertension in the setting of small for gestational age (SGA) infants⁷ or with iatrogenic reduction in elevated blood pressure.^8,9 An explanation of such findings might relate to differences in placental nutrient and oxygen transfer between hypertensive and normotensive mothers. The reduced ability of the maternal arterial supply of the placenta to autoregulate flow at the intervillous level means that changes in maternal blood pressure will be reflected within the intervillous space. Syndromes that improve perfusion at this level may improve maternal-fetal transfer of nutrients and oxygen and should be reflected in improved neonatal and infant health. Note that, certainly, a continuum must exist at which such an increase in perfusion to the villous spaces becomes maladaptive, or constitutes a "biological overshoot" and increases the risk to the mother and/or fetus. We postulate that, in the setting of SGA, as a common example of presumed decreased uteroplacental supply, neonatal morbidity is improved in hypertensive versus normotensive pregnancies.

	MATERIALS AND METHODS

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The research protocol was submitted to and approved by the University of British Columbia Ethics Board. The data for the study originate from the Canadian Neonatal Network database,¹⁰ which contains neonatal intensive care unit (NICU) data on neonates admitted to 17 tertiary care units in Canada from January 8, 1996, to October 31, 1997. From this population, we selected for study all singleton SGA infants born between 24 and 42 weeks of gestation. Small for gestational age was defined as birth weight less than the 10th percentile for gestational age by using the Whitfield chart.¹⁰ We excluded 35 infants who were moribund on admission because an explicit decision was made not to provide life support at the time of NICU admission.

The Canadian Neonatal Network database incorporates a neonatal illness severity score entitled SNAP-II (Score of Neonatal Acute Physiology).¹¹ The SNAP score is calculated within 12 hours of admission to a NICU and quantifies 6 physiologic variables: temperature, blood pressure (BP), Pao₂, serum pH, the presence of seizures, and urine output. The score ranges from 0 to 115, with higher scores reflecting more perturbed neonatal physiology. The SNAP-II measure has been shown to predict neonatal mortality and adverse perinatal outcomes in the Canadian and 2 U.S. populations.^11,12 We analyzed the relation between SNAP-II (dependent variable) and maternal hypertension (yes/no), adjusting for potential confounders: maternal age, parity, gestational age at birth, gender, major/minor congenital anomalies, outborn status, delivery by cesarean (yes/no), and antenatal steroid exposure.

For infants entering the cohort, survival was determined for SGA infants not moribund on NICU admission. Survival without severe intraventricular hemorrhage was defined as the avoidance of both neonatal mortality and an intraventricular hemorrhage of grade III or more. This was chosen as a marker of neonatal morbidity because of its association with adverse long-term sequelae, its occurrence close to birth, and, therefore, its relative independence of an infant's NICU course. We analyzed the relation between survival and survival without severe intraventricular hemorrhage (dependent variables) and maternal hypertension (yes/no), adjusting for the same potential confounders.

Pregnancy hypertension is usually defined as a blood pressure of 140/90 mmHg or greater, taken on 2 occasions more than 4 hours apart. Hypertension in pregnancy refers to a broad spectrum of conditions from pre-existing hypertension and mild gestational (pregnancy-induced) hypertension to severe gestational hypertension, eclampsia, the hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome,¹³ and multiorgan failure.¹⁴ The Canadian Neonatal Network data do not currently discriminate between forms of maternal hypertension.

We confirmed our assumption that most SGA infants admitted to NICU would be born to women with gestational hypertension or preeclampsia by search of the British Columbia Women's Hospital database of International Classification of Diseases, 9th Revision, codes. British Columbia Women's is a tertiary center, where over 80% of maternal hypertension is pregnancy-induced (ie, 792 of 940 [84.3%] cases of hypertension in pregnancy for deliveries at BC Women's Hospital, September 1, 1998, to August 31, 2000). We also reviewed the charts of the 218 inborns in the Canadian Neonatal Network database from BC Women's; 91.3% of hypertensive mothers had gestational (pregnancy-induced) hypertension, with 83.3% of it being preeclampsia (ie, gestational hypertension with proteinuria or end-organ complications such as HELLP syndrome).

Statistical analysis was carried out using SPSS 12.0 (SPSS Inc, Chicago, IL) and SAS 8.02 (SAS Institute, Cary, NC). In univariate analysis, comparisons (between SGA infants born to normotensive and those to hypertensive mothers) were made for binary variables (eg, infant gender) by unpaired t test, and for continuous variables (eg, gestational age) by Pearson correlation. P < .05 was considered to be statistically significant. We used ordinal regression to fit a cumulative logit model to the lower SNAP-II with the variables that were significant by univariate analysis. Multivariable logistic regression analysis was used for the dependent variables of neonatal survival and neonatal survival without severe intraventricular hemorrhage.

	RESULTS

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Based on inclusion and exclusion criteria, we identified 3,244 eligible SGA infants, 21.5% of whom were born to mothers with hypertension. When more stringent definitions of SGA were used, the proportion of SGA infants born to hypertensive mothers did not differ: 21.0%, when SGA was defined as less than the 5th percentile, and 21.1%, when defined as less than the 3rd percentile. The maternal and infant demographics for the whole cohort are presented in Table 1. Most SGA infants in both groups were born at or near term.

Univariate analysis of perinatal variables in the prediction of day 1 SNAP-II score revealed that the candidate variables for multivariable analysis were antenatal steroid treatment, gestational age at delivery, 5-minute Apgar score less than 7, male gender, major/minor congenital anomalies, maternal hypertension, and birth weight. Of note, antenatal corticosteroid administration was associated with worse (ie, higher) SNAP-II score, even among only those infants born at less than 33 weeks of gestation.

Table 2 shows the results of the ordinal regression; the likelihood ratio test statistics yielded P < .001, proving that the model is valid. The cumulative OR and 95% Wald CI from the ordinal regression revealed that the following independent variables were associated with a lower odds of a healthier neonate (ie, lower day 1 SNAP-II score): antenatal steroid treatment, low gestational age, poor 5-minute Apgar score, male gender, and major/minor congenital anomalies. Maternal hypertension was associated with higher odds of a healthier neonate (as reflected by a lower day 1 SNAP-II score). These results were unchanged when infants with congenital anomalies were removed from the database before analysis (data not shown).

Being delivered of a hypertensive mother was associated with an almost doubling of survival among SGA infants admitted to NICU. There was borderline significance (P = .06) in the association between being SGA and having increased survival without severe intraventricular hemorrhage (Tables 3 and 4).

	DISCUSSION

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION APPENDIX REFERENCES

A similar improvement in outcomes has been observed outside the neonatal period. McCowan et al⁷ studied 193 pregnancies complicated by SGA: 73 of these children were delivered of mothers who developed pregnancy-induced hypertension, whereas the other 120 mothers remained normotensive. Although those infants whose mothers developed hypertension were delivered, on average, 2 weeks earlier and 400 g lighter, when birth weight and gestational age were factored into the multivariable analysis, those infants whose mothers were hypertensive had better Bayley Mental Developmental Index scores at 18 months. Further support for a potentially adaptive role of hypertension comes from the literature dealing with therapy of mild-to-moderate hypertension. We demonstrated that the greater the treatment-induced mean difference in mean arterial blood pressure, the greater the proportion of SGA infants (P = .006).⁸ We postulate that the removal of the biological advantage created by mild-to-moderate hypertension is associated with worsening neonatal parameters.

The association between antenatal steroid treatment and higher SNAP-II may be due to a selection bias, in that infants receiving antenatal corticosteroids are more often inborn and may have received steroids because they were sicker. This finding has been previously reported,¹⁵ and the authors remain strong supporters of the evidence for antenatal steroid administration. The impact of poor Apgar scores, gestational age, male gender, and congenital anomalies on neonatal physiology were expected. This study also confirms the finding that gestational age is a more important predictor of perinatal outcomes than is birth weight, which was a significant predictor only in the univariate analysis.¹⁶

The limitations of this study include our choice of SGA as a model for decreased uteroplacental supply. We recognize that we may have included infants with decreased growth potential, based on genetic or environmental factors; it would be useful to repeat this study in a population of infants with better-characterized maternal histories and placental pathologies. Also, the Canadian Neonatal Network database does not subclassify the type of maternal pregnancy hypertension, and we have no knowledge about how that hypertension was managed. However, we have shown that the vast majority of hypertensive cases in our institution (where one of the largest NICUs is located) were indeed pregnancy-induced and, most commonly, preeclampsia. Other limitations include the fact that the Canadian Neonatal Network database only includes those infants admitted alive to a NICU; therefore, the small numbers of stillborn infants and those who failed to survive for discharge from the delivery suite are not included in this analysis, and we cannot predict how such analysis would be affected.

In summary, this study supports a growing body of evidence that maternal hypertension, particularly pregnancy-induced hypertension, may serve some adaptive role for the fetus in the face of uteroplacental dysfunction. This has implications for clinical management, for it follows that it must not be automatically assumed that normalization of mild-to-moderate hypertension in pregnancy is of greater benefit than risk to the fetus.

	APPENDIX

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Members of the Canadian Neonatal Network

Coordinator: Shoo K. Lee, Coordinator, Canadian Neonatal Network, Vancouver, British Columbia.

Network members: Wayne Andrews, Charles A. Janeway Child Health Centre, St. John's, Newfoundland; Ranjit Baboolal, North York Hospital, Toronto, Ontario; Jill Boulton, St. Joseph's Health Centre, London, Ontario (previously at Mount Sinai Hospital, Toronto, Ontario); David Brabyn, Royal Columbian Hospital, New Westminster, British Columbia; David S. C. Lee, St. Joseph's Health Centre, London, Ontario; Derek Matthew, Victoria General Hospital, Victoria, British Columbia; Douglas D. McMillan, Foothill's Hospital, Calgary, Alberta; Christine Newman, Hospital for Sick Children, Toronto, Ontario; Arne Ohlsson, Mount Sinai Hospital, Toronto, Ontario (formerly at Women's College Hospital, Toronto, Ontario); Abraham Peliowski, Royal Alexandra Hospital, Edmonton, Alberta; Margaret Pendray, Children's and Women's Health Centre of British Columbia, Vancouver, British Columbia; Koravangattu Sankaran, Royal University Hospital, Saskatoon, Saskatchewan; Barbara Schmidt, Hamilton Health Sciences Corporation, Hamilton, Ontario; Mary Seshia, Health Sciences Centre, Winnipeg, Manitoba; Anne Synnes, Children's and Women's Health Centre of British Columbia, Vancouver, British Columbia (formerly at Montreal Children's Hospital, Montreal, Quebec); Paul Thiessen, Children's and Women's Health Centre of British Columbia, Vancouver, British Columbia; Robin Walker, Children's Hospital of Eastern Ontario and The Ottawa Hospital-General Campus, Ottawa, Ontario; and Robin Whyte, IWK-Grace Health Centre for Women, Children and Families, Halifax, Nova Scotia.

Staff members, Canadian Neonatal Network Coordinating Centre: Li-Yin Chien, Joanna Sale, Herbert Chan, and Shawn Stewart, Vancouver, British Columbia.

	Footnotes

 
* For a list of other members of the Canadian Neonatal Network, see the Appendix.

This study was supported by grants 40503 and 00152 from the Medical Research Council of Canada. Additional funding was provided by the BC's Children's Hospital Foundation; the Calgary Regional Health Authority; the Dalhousie University Neonatal–Perinatal Research Fund; the Division of Neonatology, Children's Hospital of Eastern Ontario; the Child Health Program, Health Care Corporation of St. John's; the Neonatology Program, Hospital for Sick Children; the Lawson Research Institute; Midland Walwyn Capital Inc; the Division of Neonatology, Hamilton Health Sciences Corporation; Mount Sinai Hospital; the North York General Hospital Foundation; Saint Joseph's Health Centre, London, Ontario; the University of Saskatchewan Neonatal Research Fund; the University of Western Ontario; and Women's College Hospital.

P.v.D. is the recipient of an Investigatorship Award from the BC Research Institute for Children's and Women's Health. L.A.M. is a Michael Smith Foundation for Health Research Scholar. S.K.L. is a Medical Research Council of Canada Scholar.

Corresponding author: Dr. Laura A. Magee, BC Women's Hospital and Health Centre, 4500 Oak Street, Room 1U59, Vancouver, BC V6H 3N1; e-mail: LMagee{at}cw.bc.ca.

doi:10.1097/01.AOG.0000171121.31564.14

	REFERENCES

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1. Department of Health. Report on confidential enquiries into maternal deaths in the United Kingdom 1982–1984. London (UK): Her Majesty's Stationery Office; 1989.

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4. Department of Health. Report on confidential enquiries into maternal deaths in the United Kingdom 1991–1993. London (UK): Her Majesty's Stationery Office; 1996.

5. Department of Health. Why women die. Report on confidential enquiries into maternal deaths in the United Kingdom 1994–1996. London (UK): Her Majesty's Stationery Office; 1999.

6. National Institute for Clinical Excellence. Why women die. Report on confidential enquiries into maternal deaths in the United Kingdom, 1997–1999. London (UK): Royal College of Obstetricians and Gynaecologists Press; 2001.

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8. von Dadelszen P, Logan AG, Ornstein MP, Bull S, Koren G, Magee LA. Fall in mean arterial pressure and fetal growth restriction in pregnancy hypertension. Lancet 2000;355:87–92.[Medline]

9. Hauth JC, Ewell MG, Levine RJ, Esterlitz JR, Sibai B, Curet LB, et al. Pregnancy outcomes in healthy nulliparas who developed hypertension. Calcium for Preeclampsia Prevention Study Group. Obstet Gynecol 2000;95:24–8.[Abstract/Free Full Text]

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11. Richardson DK, Corcoran JD, Escobar GJ, Lee SK. SNAP-II and SNAPPE-II: simplified newborn illness severity and mortality risk scores. J Pediatr 2001;138:92–100.[Medline]

12. Chien LY, Whyte R, Thiessen P, Walker R, Brabyn D, Lee SK. SNAP-II predicts severe intraventricular hemorrhage and chronic lung disease in the neonatal intensive care unit. J Perinatol 2002;22:26–30.[Medline]

13. Weinstein L. Syndrome of hemolysis, elevated liver enzymes, and low platelet count: a severe consequence of hypertension in pregnancy. Am J Obstet Gynecol 1982;142:159–67.[Medline]

14. von Dadelszen P, Magee LA, Marshall JR, Rotstein OD. The maternal syndrome of preeclampsia: a forme fruste of the systemic inflammatory response syndrome. Sepsis 2000;4:43–7.

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